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Ketamine for Treatment Resistant Depression: From Research to Clinical Practice
Rayan K. Al Jurdi, MD
Brain Health Consultants Co-founder
Clinical Associate Professor
Menninger Department of Psychiatry & Behavioral Sciences
Baylor College of Medicine
Disclosure:
• Research Contracts: Janssen Pharmaceuticals, Inc., NeoSync, Inc.
• Treatment-Resistant Depression (TRD) Speaker Bureau, Janssen Pharmaceuticals, Inc.
Objectives:
• Unmet needs of Treatment Resistant Depression (TRD)
• Discuss efficacy data of ketamine for TRD
• Review of efficacy and safety data of Spravato (esketamine) for TRD and its use in clinical practice
• ketamine suggested mechanism of action
MDD is a Serious Disease with Far-Reaching Impact
• Global health problem, >300 million worldwide,1 >17 million in US2
• Almost 50% of patients suffer from treatment resistant depression (TRD) defined as: inadequate response to at least 2 antidepressants of adequate dose and duration4
• 65% report a significant inability to function in life2
• Major cause of disability in US2 and worldwide5
• MDD increases the risk for other physical and psychiatric illnesses6
• MDD worsens the outcomes of other general medical and mental conditions
• 10-year reduction in life-expectancy7
1. WHO News Release 30 Mar 2017; 2. NIMH Mental Health Website release November 2017; 3. Rush AJ et al. Am J Psychiatry . 2006;163(11):1905-1917; 4. Agency for Healthcare Research and Quality. https://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id105TA.pdf; 5. Global Burden of Disease 2010; 6. Taksler GB et al. Am J Public Health. 2017;107(10):1653–1659; 7. Walker ER, McGee RE, Druss BG. JAMA Psychiatry. 2015;72:334-341.
Consequences of TRD as Compared to MDD
1. Amos T, Witt, EA, Alphs L, et al. Poster Presented at: 29th Annual US Psychiatric & Mental Health Congress, October 21-24, 2016; San Antonio, Texas;2. Amos TB, Tandon N, Lefebvre P, et al. (2018). J Clin Psychiatry;3. Feldman RL, Dunner DL, Muller JS, Stone DA (2012). J Med Econ.
More comorbidities
(e.g., hypertension, diabetes, hear failure)1
2xHospitalization rate2
36% longer mean hospital length of stay2
7-fold Increase in suicide
rate3
Challenges with TRD:
Rush AJ et al. Am J Psychiatry . 2006;163(11):1905-1917.
Time to remission: 5-7 weeks
Current Treatments Fail to Address Patient Needs
• Current antidepressant offer1:• slow onset of action• suboptimal remission rates• substandard relapse rates
• All current pharmacotherapies target the same mechanism of action• MDD/TRD likely a heterogeneous disease that goes beyond monoamines
• Only 1 pharmacotherapy (olanzapine/fluoxetine combination) approved for TRD2
• Significant weight gain, movement disorder side effects3
• Only 1 somatic therapy (Transcranial Magnetic Stimulation) approved for TRD• Limited data on efficacy4 and long-term benefit 5
• Other treatments do not meet patient needs (e.g., Electroconvulsive therapy)• Anesthesia required, potential for severe side effects like memory loss
1. Moser G, Pink Sheet: Major Depressive Disorder Patients Emphasize Long-Term Nature of Disease In Feedback Meeting, 2018; 2. Sanacora G, et al. Neuropharmacology. 2012; 62(1):63-77; 3. Philip NS, et al. Expert Opin Pharmacother. 2010 Apr; 11(5): 709–722; 4. Work Group on Major Depressive Disorder, Gelenberg, AJ, Freeman, MP, et al. Practice Guideline for the Treatment of Patients With Major Depressive Disorder. 3rd. Washington, DC: American Psychiatric Association; 2010; 5. Ont Health Technol Assess Ser. 2016; 16(5): 1–66.
2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one
‘Repurposing” off-patent
drugs offer big hopes of
new treatments
Ketamine for Depression:
The Most Important Advance
in Field in
50 Years?
Single Ketamine Treatment and Depression
Author Design Dose Control Sample Size Endpoint
Breman et al. (2000) CO 0.5mg/kg X1 IV x 40mn Placebo 8 72 hours
Mean Changes from Baseline in the HDRS
Breman et al. Biological Psychiatry. 2000; 47(4):351-354
Single Ketamine Treatment and Depression
Author Design Dose Control Sample Size Endpoint
Breman et al. (2000) CO 0.5mg/kg X1 IV x 40mn Placebo 8 72 hours
Zarate et al. (2006) CO 0.5mg/kg X1 IV x 40mn Placebo 17 24 hours
Murrough et al. (2013) Parallel 0.5mg/kg X1 x 40mn Midazolam 73 24 hours
Sos et al. (2013) CO 0.5mg/kg X1 IV x 30mn Placebo 27 24 hours
Hu et al. (2014) Parallel 0.5mg/kg X1 IV X 40mn Placebo 30 Time to response
Lapidus et al. (2014) CO 50mg IN X1 Placebo 18 24 hours
Su et al. (2017) Parallel 0.2 or 0.5 mg/kg X1 IV x 40mn Placebo 71 24 hours
Murrough JW, et al. Am J Psychiatry. 2013;170(10):1134-1142.
Single Ketamine Infusion is Superior to Psychoactive Control in TRD: Baylor/Mt Sinai Study (N = 72)
Reduction in MADRS score 24 hours after infusion was the primary outcome measure and was significantly greater for the ketamine group than for the midazolam group (P ≤ .002).
Single Infusion of Ketamine: Meta-analysis
Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966.
Single Ketamine Treatment and Depression
Author Design Dose Control Sample Size Endpoint
Breman et al. (2000) CO 0.5mg/kg X1 IV x 40mn Placebo 8 72 hours
Zarate et al. (2006) CO 0.5mg/kg X1 IV x 40mn Placebo 17 24 hours
Murrough et al. (2013) Parallel 0.5mg/kg X1 x 40mn Midazolam 73 24 hours
Sos et al. (2013) CO 0.54mg/kg X1 IV x 30mn Placebo 27 24 hours
Hu et al. (2014) Parallel 0.5mg/kg X1 IV X 40mn Placebo 30 Time to response
Lapidus et al. (2014) CO 50mg IN X1 Placebo 18 24 hours
Su et al. (2017) Parallel 0.2 or 0.5 mg/kg X1 IV x 40mn Placebo 71 24 hours
Fava et al. (2019) Parallel 0.1 - 1.0 mg/kg X1 IV x 40mn Midazolam 99 72 hours
HAM-D-6 Scores Over First 72 Hours of Different Dosed Treatments
Fava M et al. Mol Psychiatry. 2019
Multiple Ketamine Treatments and Depression
Author Sample Size FrequencyMean Time to
RelapseResponse Rate Remission Rate
Murrough JW,et al. (2013)
24 3x per week 18 days 70.8% Not reported
Shiroma PR, et al. (2014)
14 3x per week 16 days 92% 67%
Vande Voort JL et al. (2016)
12 3x per week Not reported 58.3% 41.7%
Singh JB, et al. (2016)
672x per week & 3x per week
Not reported2x/week: 69%3x/week: 54%
2x/week: 38%3x/week: 23%
Esketamine (Spravato)
SPRAVATOTM [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.
Esketamine Phase 3 Clinical Development Program in Treatment-Resistant Depression (TRD)
Study Design n Duration (wk) Main endpoints
Acute, fixed dose study (3001, TRANFORM-1)1 Double-blind, active controlled 346 4-week induction MADRS change at 4 weeks
1. Fedgchin M, et al. Poster presented at: the 9th Biennial Conference of the International Society for Affective Disorders (ISAD); September 20-22, 2018; Houston, TX. 2. Popova V, et al. Poster presented at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami FL. 3. Daly EJ, et al. Poster presented at the European College of Neuropsychopharmacology (ECNP) Congress; October 7, 2018; Barcelona, Spain.4. Wajs E, et al. Poster presented at the European College of Neuropsychopharmacology (ECNP) Congress; October 7, 2018; Barcelona, Spain. 5. Ochs-Ross R, et al. Poster presented at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami FL.
Acute, fixed dose study (3001, TRANFORM-1)
Fedgchin M, et al. Poster presented at: the 9th Biennial Conference of the International Society for Affective Disorders (ISAD); September 20-22, 2018; Houston, TX
Esketamine Phase 3 Clinical Development Program in Treatment-Resistant Depression (TRD)
Study Design n Duration (wk) Main endpoints
Acute, fixed dose study (3001, TRANFORM-1)1 Double-blind, active controlled 346 4-week induction MADRS change at 4 weeks
Acute, flexible dose study (3002, TRANSFORM-2)2 Double-blind, active controlled 223 4-week induction MADRS change at 4 weeks
1. Fedgchin M, et al. Poster presented at: the 9th Biennial Conference of the International Society for Affective Disorders (ISAD); September 20-22, 2018; Houston, TX. 2. Popova V, et al. Poster presented at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami FL. 3. Daly EJ, et al. Poster presented at the European College of Neuropsychopharmacology (ECNP) Congress; October 7, 2018; Barcelona, Spain.4. Wajs E, et al. Poster presented at the European College of Neuropsychopharmacology (ECNP) Congress; October 7, 2018; Barcelona, Spain. 5. Ochs-Ross R, et al. Poster presented at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami FL.
Acute, flexible dose study (3002, TRANSFORM-2)
Popova V, Daly EJ, Trivedi M, et al. Randomized, double-blind study of flexibly-dosed intranasal esketamine plus oral antidepressant vs. active control in treatment-resistant depression. Presented at: the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami, FL.
Esketamine Phase 3 Clinical Development Program in Treatment-Resistant Depression (TRD)
Study Design n Duration (wk) Main endpoints
Acute, fixed dose study (3001, TRANFORM-1)1 Double-blind, active controlled 346 4-week induction MADRS change at 4 weeks
Acute, flexible dose study (3002, TRANSFORM-2)2 Double-blind, active controlled 223
4-week inductionMADRS change at 4 weeks
Elderly, acute, flexible dose study (3005, TRANSFORM-3)5
Double-blind, active controlled 138 4-week induction MADRS change at 4 weeks
1. Fedgchin M, et al. Poster presented at: the 9th Biennial Conference of the International Society for Affective Disorders (ISAD); September 20-22, 2018; Houston, TX. 2. Popova V, et al. Poster presented at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami FL. 3. Daly EJ, et al. Poster presented at the European College of Neuropsychopharmacology (ECNP) Congress; October 7, 2018; Barcelona, Spain.4. Wajs E, et al. Poster presented at the European College of Neuropsychopharmacology (ECNP) Congress; October 7, 2018; Barcelona, Spain. 5. Ochs-Ross R, et al. Poster presented at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami FL.
Elderly, acute, flexible dose study (3005, TRANSFORM-3)
Ochs-Ross R, et al. Poster presented at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami FL.
Esketamine Phase 3 Clinical Development Program in Treatment-Resistant Depression (TRD)
Study Design n Duration (wk) Main endpoints
Acute, fixed dose study (3001, TRANFORM-1)1 Double-blind, active controlled 346 4-week induction MADRS change at 4 weeks
Acute, flexible dose study (3002, TRANSFORM-2)2 Double-blind, active controlled 223
4-week inductionMADRS change at 4 weeks
Elderly, acute, flexible dose study (3005, TRANSFORM-3)5
Double-blind, active controlled 138 4-week induction MADRS change at 4 weeks
Maintenance, relapse prevention study (3003, SUSTaIN 1)3
Open-label or double-blind induction (4-wks) and
optimization (12-wks), followed by double-blind, active-controlled maintenance
705Variable duration,
longer term
Time to relapse; relapse in stable remitters; relapse in
stable responders
1. Fedgchin M, et al. Poster presented at: the 9th Biennial Conference of the International Society for Affective Disorders (ISAD); September 20-22, 2018; Houston, TX. 2. Popova V, et al. Poster presented at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami FL. 3. Daly EJ, et al. Poster presented at the European College of Neuropsychopharmacology (ECNP) Congress; October 7, 2018; Barcelona, Spain.4. Wajs E, et al. Poster presented at the European College of Neuropsychopharmacology (ECNP) Congress; October 7, 2018; Barcelona, Spain. 5. Ochs-Ross R, et al. Poster presented at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami FL.
Maintenance, relapse prevention study (3003, SUSTaIN 1)
Popova V, Daly EJ, Trivedi M, et al. Randomized, double-blind study of flexibly-dosed intranasal esketamine plus oral antidepressant vs. active control in treatment-resistant depression. Presented at: the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami, FL.
Maintenance, relapse prevention study (3003, SUSTaIN 1)
Popova V, Daly EJ, Trivedi M, et al. Randomized, double-blind study of flexibly-dosed intranasal esketamine plus oral antidepressant vs. active control in treatment-resistant depression. Presented at: the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami, FL.
Esketamine Phase 3 Clinical Development Program in Treatment-Resistant Depression (TRD)
Study Design n Duration (wk) Main endpoints
Acute, fixed dose study (3001, TRANFORM-1)1 Double-blind, active controlled 346 4-week induction MADRS change at 4 weeks
Acute, flexible dose study (3002, TRANSFORM-2)2 Double-blind, active controlled 223
4-week inductionMADRS change at 4 weeks
Elderly, acute, flexible dose study (3005, TRANSFORM-3)5
Double-blind, active controlled138
4-week inductionMADRS change at 4 weeks
Maintenance, relapse prevention study (3003, SUSTaIN 1)3
Open-label or double-blind induction (4-wks) and optimization (12-wks), followed by double-blind,
active-controlled maintenance
705Variable duration,
longer term
Time to relapse; relapse in stable remitters; relapse in stable
responders
Maintenance, safety study (3004, SUSTaIN 2)4 Open-label 802 52-weeks Safety and tolerability
1. Fedgchin M, et al. Poster presented at: the 9th Biennial Conference of the International Society for Affective Disorders (ISAD); September 20-22, 2018; Houston, TX. 2. Popova V, et al. Poster presented at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami FL. 3. Daly EJ, et al. Poster presented at the European College of Neuropsychopharmacology (ECNP) Congress; October 7, 2018; Barcelona, Spain.4. Wajs E, et al. Poster presented at the European College of Neuropsychopharmacology (ECNP) Congress; October 7, 2018; Barcelona, Spain. 5. Ochs-Ross R, et al. Poster presented at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP); May 29-June 1, 2018; Miami FL.
Maintenance, safety study (3004, SUSTaIN 2)
24.0%
38.1% 37.8%
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
45.0
Weekly Dosing Throughout One Change from Weekly to EOW Change Back and Forth fromWeekly to EOW
Wajs E, et al. Poster presented at the European College of Neuropsychopharmacology (ECNP) Congress; October 7, 2018; Barcelona, Spain.
Spravato (Esketamine)
SPRAVATOTM [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.
FDA Approved: March 5, 2019
SPRAVATOTM is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist indicated, in a conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (TRD) in adults.
INDUCTION
Weeks 1-4
(twice weekly)
• Day 1: 56 mg
• Subsequent doses: 56 mg or 84 mg
MAINTENANCE
Weeks 5-8
(once weekly)
• 56 mg or 84 mg once weekly
CONTINUATION
Weeks 9+
(once or EOW)
• 56 mg or 84 mg every 2 weeks or once weekly
Ad
vers
e E
ven
tsSpravato + AD
(N=346)Placebo + AD
(N=222)
Dissociation 142 (41%) 21 (9%)
Dizziness 101 (29%) 17 (8%)
Nausea 98 (28%) 19 (9%)
Sedation 79 (23%) 21 (9%)
Vertigo 78 (23%) 6 (3%)
Headache 70 (20%) 38 (17%)
Dysgeusia 66 (19%) 30 (14%)
Hypoesthesia 63 (18%) 5 (2%)
Anxiety 45 (13%) 14 (6%)
Lethargy 37 (11%) 12 (5%)
↑Blood Pressure 36 (10%) 6 (3%)
Vomiting 32 (9%) 4 (2%)
Insomnia 29 (8%) 16 (7%)
Nasal Discomfort 23 (7%) 11 (5%)
Spravato + AD (N=346)
Placebo + AD (N=222)
Diarrhea 23 (7%) 13 (6%)
Throat Irritation 23 (7%) 9 (4%)
Feeling Drunk 19 (5%) 1 (0.5%)
Dry Mouth 19 (5%) 7 (3%)
Hyperhidrosis 14 (4%) 5 (2%)
Dysarthria 15 (4%) 0 (0%)
Pollakiuria 11 (3%) 1 (0.5%)
Oropharyngeal Pain 9 (3%) 5 (2%)
Mental Impairment 11 (3%) 2 (1%)
Tremor 12 (3%) 2 (1%)
Euphoric Mood 15 (4%) 2 (1%)
Constipation 11 (3%) 3 (1%)
Feeling Abnormal 12 (3%) 0 (0%)
Tachycardia 6 (2%) 1 (0.5%)
SPRAVATOTM [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.
Warnings & Precautions
• Sedation• Dissociation• Abuse and Misuse• SPRAVATO Risk Evaluation and Mitigation Strategy (REMS)
• Suicidal Thoughts and Behaviors in Adolescents and Young Adults• Increase in Blood Pressure• Cognitive Impairment• Impaired Ability to Drive and Operate Machinery
• Ulcerative or Interstitial Cystitis• Embryo-fetal Toxicity
Ketamine and Suicidal Ideation
0
10
20
30
40
50
60
70
Day 1 Day 2 Day 3 Day 7
Clinician-Administered Measures
Ketamine Control
Wilkinson S, et al. AM J Psychiatry 2018; 175 (2): 150-158.
***** ***
**
*p<0.05 **p<0.01 ***p<0.001
0
10
20
30
40
50
60
70
Day 1 Day 2 Day 3 Day 7
Self-Reported Measures
Ketamine Control
*** ****
Ketamine and NMDA Receptor
Neill J et al. European Neuropsychopharmacology. 2014;24(5):822-835.
Suggested Mechanism of Action
Duman RS. Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide [version 1; peer review: 3 approved]. F1000Research 2018, 7(F1000 Faculty Rev):659 (https://doi.org/10.12688/f1000research.14344.1)
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